Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. HCC is the sixth most common cancer and the third most common cause of cancer mortality in the world (Yang J D, et al., (2010) Nat Rev Gastroenterol Hepatol 7: 314 448-458). Many molecular targeted drugs have entered clinical trials as palliative and adjuvant treatments for HCC (Villanueva A, et al., (2011) Gastroenterology 140: 316 1410-1426). The multikinase inhibitor sorafenib was approved for the first-line therapy in advanced HCC as a result of a statistically significant but modest improvement of overall survival and time to progression in two randomized controlled trials (Llovet J M, et al., (2008) N Engl J Med 359: 378-390 and Cheng A L, et al., (2009) Lancet Oncol 10: 25-34). Other molecular targeted drugs have been tested in combination with sorafenib or in the adjuvant setting (Zhu A X (2012), Semin Oncol 39: 493-502. and Huynh H (2010) Biochem Pharmacol 80: 550-560). However, it is well-known in the art that the benefits of current molecular targeted agents including sorafenib are very limited. The response rate in the phase III clinical trial using sorafenib is very low, i.e., only 2.3% to 3.30% (Villanueva A, et al., (2012) Clin Cancer Res 18: 1824-1826).
Biomarkers are increasingly used for diagnosis, prognosis, and therapeutic decision making in diverse cancers, propelling a paradigm shift in the management of cancer. Biomarkers have helped to stratify patients and thus achieve better outcomes from a given drug in the clinic Trastuzumab, a HER2 targeting monoclonal antibody, is effective in metastatic breast cancer patients with 3+ HER2 over-expression assessed by immunohistochemistry (IHC) or HER2 gene amplification (Vogel C L, et al., (2002) J Clin Oncol 20: 719-726). Also, patients with non-small cell lung cancer harboring activating mutations within the kinase domain of EGFR show impressive clinical responses to the EGFR inhibitor gefitinib (Lynch T J, et al., N Engl J Med 350: 2129-2139). This type of molecular classification which stratifies individual tumors into molecular subtypes for which targeted therapy could have potential efficacy is described as actionable molecular subtyping (West L, et al., PLoS One 7: e31906. and Vidwans S J, et al., PLoS One 6: e18257).